STRING: Protein association networks Lars Juhl Jensen
interaction networks
association networks
guilt by association
protein networks
STRING
9.6 million proteins
common foundation
Exercise 1 Go to http://string-db.org/ Query for human insulin receptor (INSR) using the search by name functionality Make sure you are in evidence view" (check the buttons below the network) Why are there multiple lines connecting the same to two proteins?
curated knowledge
(what we know)
protein complexes
3D structures
pathways
metabolic pathways
Letunic & Bork, Trends in Biochemical Sciences, 2008
signaling pathways
very incomplete
experimental data
(what we measured)
physical interactions
Long Yeast two-hybrid Bait Prey 0.2 0.1 Nuclear Hydrophobic Protein-fragment complementation assay Transmembrane Disordered Cytosolic TAP tag Co-purified proteins Bait Prey Reconstituted enzyme Basic Abundant Bait Tandem affinity purification Jensen & Bork, Science, 2008
genetic interactions
Beyer et al., Nature Reviews Genetics, 2007
gene coexpression
microarrays
RNAseq
Exercise 2 (Continue from where exercise 1 ended) Which types of evidence support the interaction between INSR and IRS1? Click on the interaction to view the popup, which has buttons linking to full details Which types of experimental assays support the INSR IRS1 interaction?
predictions
(what we infer)
genomic context
evolution
gene fusion
Korbel et al., Nature Biotechnology, 2004
gene neighborhood
Korbel et al., Nature Biotechnology, 2004
phylogenetic profiles
Korbel et al., Nature Biotechnology, 2004
a real example
Cell Cellulosomes Cellulose
complications
many databases
different formats
different identifiers
variable quality
not comparable
not same species
hard work
parsers
mapping files
quality scores
affinity purification
von Mering et al., Nucleic Acids Research, 2005
phylogenetic profiles
score calibration
gold standard
von Mering et al., Nucleic Acids Research, 2005
implicit weighting by quality
common scale
homology-based transfer
orthologous groups
Franceschini et al., Nucleic Acids Research, 2013
missing most of the data
Exercise 3 (Continue from where exercise 2 ended) Change the network to the confidence view Change the confidence cutoff to 0.9; any changes in proteins or interactions shown? Turn off all but experiments; what changes? Increase the number of interactors shown to 50; how many proteins do you get? Why?
text mining
>10 km
too much to read
exponential growth
~40 seconds per paper
computer
as smart as a dog
teach it specific tricks
named entity recognition
comprehensive lexicon
cyclin dependent kinase 1
CDC2
orthographic variation
expansion rules
prefixes and suffixes
CDC2
hcdc2
flexible matching
spaces and hyphens
cyclin dependent kinase 1
cyclin-dependent kinase 1
black list
SDS
information extraction
co-mentioning
counting
within documents
within paragraphs
within sentences
scoring scheme
score calibration
NLP Natural Language Processing
part-of-speech tagging
what you learned in school pronoun pronoun verb preposition noun
semantic tagging
grammatical analysis
Gene and protein names Cue words for entity recognition Verbs for relation extraction [ nxexpr The expression of" [ nxgene the cytochrome genes" [ nxpg CYC1 and CYC7]]]" is controlled by" [ nxpg HAP1] Saric et al., Proceedings of ACL, 2004
type and direction
complex sentences
anaphoric references
it
summary
association networks
heterogeneous data
common identifiers
quality scores
protein networks
string-db.org Szklarczyk et al., Nucleic Acids Research, 2015
STITCH
chemical networks
stitch-db.org Kuhn et al., Nucleic Acids Research, 2014
COMPARTMENTS
subcellular localization
compartments.jensenlab.org Binder et al., Database, 2014
TISSUES
tissue expression
tissues.jensenlab.org Santos et al., PeerJ, 2015
DISEASES
disease associations
diseases.jensenlab.org Frankild et al., Methods, 2015
Exercise 4 Open http://tissues.jensenlab.org Look up tissue associations for insulin (INS) Open http://diseases.jensenlab.org Search for insulin receptor (INSR) What is the strongest associated disease? Inspect the underlying text-mining evidence